1. Field of the Invention
Provided herein are crystal polymorphs of a factor Xa inhibitor and compositions and methods thereof.
2. State of the Art
Factor Xa is a serine protease, the activated form of its precursor factor X, and a member of the calcium ion binding, gamma carboxyglutamic acid (GLA)-containing, vitamin K dependent, blood coagulation factors. Factor Xa appears to have a single physiologic substrate, namely prothrombin. Since one molecule of factor Xa may be able to generate greater than 1000 molecules of thrombin (Mann, et al., J. Thrombosis. Haemostasis 1: 1504-1514, 2003), direct inhibition of factor Xa as a way of indirectly inhibiting the formation of thrombin has been considered an efficient anticoagulant strategy.
Several classes of small molecule factor Xa inhibitors have been reported, for example, in U.S. Pat. Nos. 7,521,470, 7,696,352, and 7,763,608, U.S. Patent Application Publication Nos. 2007/0066615, 2008/0293704, and 2008/0051578, all of which are incorporated by reference in their entirety.
U.S. Pat. No. 6,376,515 B2 discloses a specific factor Xa inhibitor compound identified in Example 206, which is also disclosed in U.S. Pat. No. 6,835,739 B2 as Example 206 and herein identified as betrixaban. The structure of betrixaban is represented by Formula I:

In addition, U.S. Pat. No. 7,598,276 (the '276 patent) describes salts and a crystalline polymorph of a maleate salt of betrixaban (also referred to as Form I). U.S. Pat. Nos. 6,376,515, 6,835,739 and 7,598,276 are incorporated by reference in their entirety.